Adult Mouse Leptomeninges Exhibit Regional and Age-related Cellular Heterogeneity Implicating Mental Disorders
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE242810 | GEO | 2023/09/10
REPOSITORIES: GEO
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Project description:The leptomeninges envelop the central nervous system and contribute to brain homeostasis by producing trophic factors and regulating entrance of cells, factors and agents, immune responses and cerebrospinal fluid production. We report that leptomeninges from adult mice are regionally patterned. Leptomeninges dissected from anterior or posterior aspects of the forebrain grown in hetero- or homo-typic culture with anterior and posterior cortical cells demonstrate differences in ability to support survival of neuronal subsets and proliferation of progenitors for astrocytes and oligodendrocytes. Meningeal support changes with age: co-culture with 18-month old leptomeninges reduced numbers of cortical progenitor cells and neurons but increased astrocyte expansion. Analysis of cytokine secretion and single cell RNA-sequencing revealed differences in anterior versus posterior, young versus old meningeal factors and composition. These data demonstrate that adult leptomeninges are regionally patterned in cell composition and functional properties, and suggest that meningeal deficits may contribute to brain aging and disease.
2021-11-01 | GSE139922 | GEO
Project description:<p>Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with regional phenotypes. </p> <p>Reprinted from <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=25446321">Whitmore, S.S., Wagner, A.H., DeLuca, A.P., Drack, A.V., Stone, E.M., Tucker, B.A., Zeng, S., Braun, T.A., Mullins, R.F., Scheetz, T.E., 2014. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq. Experimental Eye Research</a>. Used under <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported </a>license.</p> <p>Additional RNA sequencing was performed on temporal, macular, nasal, inferior, and superior retina from a fifth subject and is included in this dataset. See original publication for details.</p>
| phs001151 | dbGaP
Project description:Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here we used high-throughput single nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in the extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases – for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the new data complete a “Version 1” cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.
2023-07-12 | GSE236566 | GEO
Project description:The meninges, comprising the leptomeninges (pia and arachnoid layers) and the pachymeninx (dura layer), participate in CNS autoimmunity but their relative contributions remain unclear. Here, we report on findings in animal models of CNS autoimmunity and in multiple sclerosis patients, where, in chronic disease, the leptomeninges were highly inflamed and showed structural changes, while the dura mater was only marginally affected. Although dural vessels were leakier than leptomeningeal vessels, effector T cells adhered more weakly to the dural endothelium. Furthermore, local antigen presenting cells presented myelin and neuronal autoantigens less efficiently and the activation of autoreactive T cells was lower in dural than leptomeningeal layers, preventing local inflammatory processes. Direct antigen application was required to evoke a local inflammatory response in the dura. Together, our data demonstrate an uneven involvement of the meningeal layers in CNS autoimmunity, in which effector T cell trafficking and activation are functionally confined to the leptomeninges, while the dura remains largely shielded from CNS autoimmune processes.
2022-07-04 | GSE203046 | GEO
Project description:The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid and pial. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial sub-population marked by expression of µ-Crystallin. Developmental analysis reveals a progressive, ventral to dorsal maturation of telencephalic meninges. Our studies present an unprecedented view of meningeal fibroblasts, providing a molecular profile of embryonic meningeal fibroblasts by layer that yield insights into mechanisms of meninges development and function.
2020-07-06 | GSE150219 | GEO
Project description:Adult (6- to 8-week-old) C57BL/6 purchased from CLEA Japan Inc. (Tokyo, Japan) were used as donors ocular pigment epithelium (PE). To cultivate retinal PE (RPE) eyes were cut into two parts along a circumferential line posterior to the ciliary process, creating a ciliary body-deficient posterior eyecup. The eyecup was then incubated in 0.2% trypsin (Biowhitaker) for 1 hr. These tissues were triturated to make a single cell suspension, and then re-suspended in the medium. Experiment Overall Design: Comparison of gene expression pattern in Mouse Primary Cultured Cell Lines (RPE, RPE+IFNg).
2008-11-13 | E-GEOD-9428 | biostudies-arrayexpress
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217312 | GEO
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217276 | GEO
Project description:AbstractBlindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including age related macular degeneration, dysregulated immune response mediated retinal degeneration have been found to play a critical role in the disease pathogenesis. To better understand the pathogenic mechanisms underlying the retinal degeneration, we used a mouse model of systemic immune activation where we infected mice with lymphocytic choriomeningitis virus (LCMV) clone 13. Here we evaluated the effects of LCMV infection and present a comprehensive discovery-based proteomic investigation using tandem mass tag (TMT) labelling and high-resolution liquid chromatography - tandem mass spectrometry (LC-MS/MS). Changes in protein regulation in the posterior part of the eye, neuroretina and RPE/choroid, were compared to spleen as a secondary lymphoid organ and to the kidney as a non-lymphoid but encapsulated organ at 1, 8 and 28 weeks of infection. Using bioinformatic tools, we found several proteins responsible for maintaining normal tissue homeostasis to be differentially regulated in the neuroretina and the RPE/choroid during the degenerative process. Additionally, in the organs we observed several important protein pathways contributing to cellular homeostasis and tissue development to be perturbed and associated with LCMV mediated inflammation promoting disease progression. Our findings suggest that the response to a systemic chronic infection differs between neuroretina, and the RPE/choroid and the processes induced by chronic systemic infection in RPE/choroid are not unlike those induced in non-immune privileged organs such as the kidney and spleen. Overall, our data provides detailed insight into several molecular mechanisms of retinal degeneration and highlights various novel proteins pathways which further suggest that the posterior part of the eye is not an isolated immunological entity despite of the existence of neuroretinal immune privilege.
2024-03-22 | PXD050187 | Pride
Project description:To characterize underlying changes in the retinal pigment epithelium (RPE)/choroid with age, we produced gene expression profiles for the RPE/choroid and compared the transcriptional profiles of the RPE/choroid from young and old mice. The changes in the aged RPE/choroid suggest that the tissue has become immunologically active. Such phenotypic changes in the normal aged RPE/choroid may provide a background for the development of age-related macular degeneration. Experiment Overall Design: We compared the gene expression of retinal pigmental epithelium/choroid from young and old animals. There were 4 samples from young mice and 4 samples from old mice. Each sample contained 4 retinal pigmental epithelium/choroid from 2 animals
2008-06-11 | E-GEOD-10965 | biostudies-arrayexpress